tbuckley/cabot-search huggingface dataset:
An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab and bevacizumab therapy in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.
Authors: Tanios S. Bekaii-Saab, Mark Yarchoan, Muneeb Ahmed, David Michael Cohan, Wen Wee Ma
Journal: Journal of Clinical Oncology (2023)

TPS4178 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of bevacizumab (Bev) and atezolizumab (Atezo) is the preferred frontline therapy for advanced HCC, but a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment, mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the tumor microenvironment is intended to provide systemic antitumor activity and enhance therapeutic response to anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP3 with Bev. This study will evaluate the safety and efficacy of RP3 combined with Atezo and Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC. Methods: The 1L and 2L cohorts will each enroll up to 30 pts. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following one prior line of systemic therapy, which must have included a PD-1/PD-L1−directed agent. Key inclusion criteria include advanced, unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh Class A, and Eastern Cooperative Oncology Group performance status of 0−1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of tumor into any major blood vessel(s) and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in the 1L cohort will receive 1200 mg Atezo and 15 mg/kg Bev every 3 weeks (Q3W) together with RP3 intratumorally Q3W for a total of up to 8 doses. Pts in the 2L cohort will receive RP3 every 2 weeks for 4 doses with Bev Q3W starting on cycle (C) 1 day (D) 1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint is overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .
Serum vitamin B12 levels and response to immunotherapy.
Authors: Ilit Turgeman, Anat Reiner Benaim, Stav Regev Tsur, Haya Chahine, Gil Bar-Sela
Journal: Journal of Clinical Oncology (2023)

e14542 Background: Underlying metabolic pathways have a role in regulation of response to cancer immunotherapy. Due to its immunomodulatory properties, we sought to investigate the relationship between elevated serum vitamin B12 (VitB12) and survival among individuals with cancer treated with immune checkpoint inhibitors. Methods: Data from a retrospective chart review were used to identify patients with advanced cancer initiating anti-neoplastic treatment and a concomitant VitB12 measurement (elevated: &gt; 820 ng/L), between 1/2010-1/2022 at our institution. Patients on immunotherapy (IO) and other regimens (control) were compared using Mann-Whitney test for continuous variables, and Chi-square test or Fisher's test for categorical variables. Multivariate Cox regression models were used to assess the effect of VitB12 levels on overall survival (OS) and progression free survival (PFS), with adjustment for potential confounders. Results: A total of 501 patients were included (control, n = 408; IO, n = 93). Groups were well balanced for treatment line (first line, 91.4% vs. 94%), VitB12 levels (elevated, 29.9% vs. 23.7%; mean, 762.4 ng/L vs. 687.6 ng/L) and liver function tests. Cancer diagnoses differed between groups (most common, gastrointestinal vs. lung, p &lt; 0.001). Multivariate analysis revealed that high VitB12 was negatively associated with OS in both groups (control: hazard ratio, HR 1.4, 95% CI 1.01-1.96, p = 0.04; IO: HR 2.74 as sum of linear baseline and interaction effects, in log scale), as were age (HR 1.03, 95% CI 1.02-1.04, p &lt; 0.01), male gender (HR 0.66, 95% CI 0.50-0.88, p &lt; 0.01), and neutrophil to lymphocyte ratio (NLR) (HR 1.05, 95% CI 0.48-0.99, p = 0.01). However, the only negative prognostic factor for PFS was VitB12 in the IO group alone (calculated HR 8.34). No association was observed with patient and cancer characteristics, other laboratory values, chemotherapy (p = 0.3) or biologic therapy (p = 0.8). Mean follow-up in the control and IO groups was 93 vs 54 weeks (OS), and 22 vs 33 weeks (PFS), respectively. Conclusions: Elevated VitB12 levels were negatively associated with response to immune checkpoint inhibitors, independently of other prognostic factors such as age, cancer type, treatment line and NLR. In addition to a direct role in cellular immunity, VitB12 is involved in gut microbiota balance, which in turn affects host immune responses – suggesting a possible immune-metabolic interplay. Further research is needed to elucidate the metabolic regulators of response to immunotherapy and potential strategies of intervention, in order to rationalize and broaden its clinical utility.
Trends in U.S and global patient enrollment from 2014 to 2022 in lung cancer clinical trials supporting marketing applications: An FDA analysis.
Authors: Oladimeji Akinboro, Vaibhav Kumar, Nicole Lauren Drezner, Erin A. Larkins, Richard Pazdur, Paul Kluetz, Harpreet Singh
Journal: Journal of Clinical Oncology (2023)

1576 Background: Oncology drug development is an increasingly global endeavor, however it is unclear how enrollment in registrational clinical trials for lung cancer have been impacted. Clinical trial data must be reflective of the intended population in order to be considered applicable to U.S patients and medical practice, and for FDA review. Methods: Registrational clinical trials supporting lung cancer indications submitted to FDA from 2014 to 2022 were included. Patient enrollment per country was extracted for each trial, and countries were grouped into 9 global regions. The proportion of patients enrolled in the U.S and global regions were calculated for each trial. For the purpose of this analysis, MRCTs were defined as trials that enrolled at least 5% of patients from each of ≥ 3 global regions with no region accounting for ≥ 70% of patient enrollment. Trial-level patient enrollment was aggregated into 3 triennia: 2014-2016, 2017-2019, and 2020-2022. Results: A total of 66 pivotal trials supporting 59 applications submitted to FDA were evaluated during the study period. Of these, 91% ( n=60) were for non-small cell lung cancer while 9% ( n=6) were for small cell lung cancer; 59% ( n=39) were randomized controlled trials (RCTs) while 41% ( n=27) were single-arm trials; 53% ( n=35) were for biologics while 47% ( n=31) were for non-biologics; and 86% ( n=30) of the biologics-based regimens were anti-programmed death (ligand)-1 antibody-containing regimens. The proportion of trials with no U.S patient enrollment increased from 4.8% in 2014-2016 to 19.0% in 2020-2022 while those with ≥ 10% U.S patient enrollment declined from 71.4% in 2014-2016 to 52.3% in 2020-2022. There was a decline in the proportion of trials conducted as MRCTs since 2014 from 85.7% in 2014-2016 to 66.7% in 2020-2022. Conclusions: This exploratory analysis suggests that there may be declining U.S patient enrollment in lung cancer pivotal trials, and the proportion of these trials conducted as MRCTs may also be declining. These patterns of decline appear to be driven by the countries selected for patient enrollment in RCTs rather than in single-arm trials. Pivotal trials that do not enroll U.S patients and are not conducted as true MRCTs may have limited applicability to U.S patients.[Table: see text]
Feasibility and clinical utility of cancer whole-genome sequencing in adult solid tumors.
Authors: Minsuk Kwon, Ryul Kim, Baek-Lok Oh, Seokhwi Kim, Jin Roh, Hoon Hur, Woo Sik Yu, Chang Woo Kim, Jeong Seok Lee, Young Seok Ju
Journal: Journal of Clinical Oncology (2023)

e15055 Background: As sequencing costs decrease, whole-genome sequencing (WGS) is expected to be utilized in actual cancer patient care. However, there is insufficient evidence that WGS can be applied to the real-world cancer patient care, and how it can help in the diagnosis and treatment process. Methods: This prospective cohort study was designed to evaluate the feasibility and clinical utility of WGS in adult solid cancer care at a tertiary hospital. All solid cancer patients who were scheduled to undergo biopsy or surgery for diagnosis or treatment were eligible for the study. Either fresh or formalin-fixed paraffin-embedded tissue with match peripheral blood were obtained. Tumors were sequenced to depth of 40x, and WGS data were curated by Genome Insight Inc. The WGS reports were provided to clinician through a web-based, user-browsable reporting system in real time. Results: 97 patients were enrolled between Sep 2022 and Jan 2023. Besides 10 QC failed cases, 87 patients were provided WGS reports. Median turn-around-time was 14 day (range 12-23). The clinical utility of WGS was evaluated in 77 cancer patients, excluding 10 cases with estimated cancer cell fraction less than 15%. 31 patients (40.3%) had more than one actionable alteration targeted by on-label drugs. 49 patients (63.6%) also had more than one actionable alteration targeted by either on-label or off-label drugs. In selected cases (N = 6), WGS could suggest the diagnosis for cancer of unknown origin or the revision of pathologic diagnosis that was regarded as a double primary cancer into a metastasis of a single cancer. By providing information of total mutation counts, whole-genome-wide mutational signature analysis, copy number variation with high accuracy, germline alterations, detection of homologous recombination deficiency, and presence of loss-of-heterozygosity, WGS could further refine the actionable mutations in 39% cases, and estimate the etiology of cancer (genomic or environmental) or to determine hereditary or sporadic cancer in 60% cases. In 90% cases, WGS demonstrated clinical utility with supporting diagnosis, informing carcinogenesis, or annotating actionable alterations. Conclusions: WGS was applicable in real-world cancer care. WGS demonstrated clinical utility in the diagnosis and treatment of adult cancer patients. Clinical trial information: KCT0008118 . [Table: see text]
Anti-PD1 antibody pucotenlimab in combination with bevacizumab or lenvatinib in a phase II study for the treatment of advanced hepatocellular carcinoma (aHCC).
Authors: Hong Zhao, Aiping Zhou, Jianfei Tu, Yuxian Bai, Xianhai Mao, Tianqiang Song, Bo Li, Wenxiang Dai, Jing Lv, Jufeng Wang, Xu Che, Lianxin Liu, Lianhai Zhang, Wei Wu, Jianqiang Cai
Journal: Journal of Clinical Oncology (2023)

e16180 Background: Immune checkpoint inhibitors plus anti-VEGFR agents have emerged as a powerful strategy for aHCC. This has been confirmed by several phase 3 trials: 1) atezolizumab + bevacizumab showed an ORR of 27.3%, mPFS of 6.8 months, and mOS of 19.2 months in IMbrave150; 2) sintilimab + IBI305 (bevacizumab biosimilar) showed an ORR of 21%, mPFS of 5.6 months and mOS of 22.1 months in Orient-32; 3) camrelizumab + Apatinib showed an ORR of 25.4%, mPFS of 5.6 months and mOS 22.1 months in SHR-1210-III-310. To our knowledge, data from a trial about PD-1 inhibitor plus different antiangiogenic drugs have not been reported. Here, we present the result of the Pucotenlimab (HX008) plus bevacizumab (B) or lenvatinib (L) as the first-line treatment for aHCC. Methods: This study is a single-arm, multiple-center trial. Eligible pts aged 18 to 75 years had 1) histologically or cytologically confirmed aHCC naïve to systemic treatment; 2) BCLC stage C or B not amenable to surgery and/or locoregional therapy or showed radiographic progression after treatment; 3) Child-Pugh class A/B7; 4) ECOG PS 0 or 1. Pts of C1 received HX008 200 mg IV Q3W plus B 15 mg/kg, IV, Q3W; Pts of C2 received HX008 (200mg IV Q3W) plus L (12mg/d for BM ≥60 kg or 8 mg/d for &lt;60 kg). The primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Between Dec. 30, 2020, and Oct. 12, 2022, 75 pts were sequentially assigned to C1 (n = 28) or C2 (n=47). The pts characteristics are presented in table below. With a median follow-up duration of 15.2 and 12.5 months, investigator-assessed ORR per RECIST v1.1 showed a similar magnitude of benefit ( p=0.6150) between C1 (28.6%) and C2 (36.2%). Also, there were no statistically significant differences (p=0.4606) in median PFS, 7.5 and 9.6 months (HR:1.26 [0.674-2.373]). OS result is not mature, the 12-mo rate was 88.6% and 81.8%. The most common TEAEs were platelet count decreased (42.9%), and proteinuria (35.7%) in C1; and platelet count decreased (44.7%), proteinuria (42.6%), and hypothyroidism (40.4%) in C2. Grade ≥3 TEAEs were reported in 9 pts (32.1%) and 24 pts (51.1%) in C1 and C2, respectively, with hypertension (10.7% and 12.9%) being the most commonly reported. The most commonly SAE reported were abdominal infection (3.6%) in C1, and diarrhea (4.3%) in C2. Conclusions: Pucotenlimab plus bevacizumab or lenvatinib has demonstrated clinical efficacy in aHCC patients naïve to systemic therapy, and no unexpected safety signals emerged. The two cohorts are comparable in terms of effectiveness, but safety profiles presented some differences. The findings need to be confirmed by additional studies. Clinical trial information: NCT04741165 . [Table: see text]
The FOR ME (Fostering Opportunities in Research through Messaging and Education) study: Developing a culturally sensitive narrative intervention to promote equity in clinical trials.
Authors: Neha Hippalgaonkar, Ryan Huu-Tuan Nguyen, Leslie Carnahan, Vida Henderson, Eliza Brumer Cohn, Tigist Mersha, Kauthar Salum, Ana Williams, Paramjeet Grewal Khosla, Anne Marie Murphy, Lolita Coleman, Beluah Brent, Kent Hoskins
Journal: Journal of Clinical Oncology (2023)

TPS6653 Background: Black women are more likely to die from breast cancer than women of any other race/ethnicity. Contributing factors to this inequity include structural and socioeconomic determinants of health, differential access to novel therapies, tumor biology and comorbidities. In 2020, only 7.2% of enrollees in clinical trials that led to approval of 3 novel drugs for breast cancer were Black. Underrepresentation of patients from racial/ethnic minority groups in clinical trials is a contributing factor to health disparities. The first aim of this study is to conduct multiple qualitative methods with multi-level stakeholders to identify barriers, facilitators, and intervention priorities that would assist Black breast cancer patients to make informed decisions about participating in clinical trials. Secondly, we aim to create a culturally sensitive, narrative intervention designed to support decision making and motivate Black breast cancer patients to participate in clinical trials. Aim 3 will pilot a study to determine acceptability of the intervention among patients and assess whether it increases clinical trial participation in a safety net oncology practice. Methods: Community-based participatory research approaches are guiding our research methodologies. First, we are conducting interviews and story circles with Black women with breast cancer, community partners and advocates, and oncologists and clinical trials office staff. These interviews will identify themes to inform intervention content. Next, interviews and focus groups will invite feedback on the educational/motivational content of the intervention and will be used to develop a culturally sensitive script and storyboards. A video production company will produce the narrative intervention. Finally, focus groups and interviews with participant cohorts will provide feedback on the completed intervention. Black women diagnosed with breast cancer will view the intervention in an oncology clinic. Using a pretest/posttest design, we will analyze the acceptability of the intervention and its effect on intention to participate in clinical trials. We will then conduct a quasi-experimental study in a safety net oncology practice to determine whether the rate of clinical trial participation among Black breast cancer patients increases following implementation of the intervention as a standard component of new patient education. Recruitment started in July 2022, and currently, 14 of 30 interviews with patients are completed. Aim 1 interviews with patients, oncologists, clinical trial staff, and advocates are expected to finish by April 2023, and results will be presented.
A prospective evaluation of pelvic radiation vs. no radiation among patients with young-onset rectal cancer: Impact on patient-reported outcomes.
Authors: Kelsey L Corrigan, Emma Holliday, Montserrat Guraieb-Trueba, Oliver Peacock, John Michael Skibber, Brian K. Bednarski, Craig Messick, Matthew Murray Tillman, Benny Johnson, Grace L. Smith, Sa Thi Nguyen, Suprateek Kundu, Alec Reinhardt, George J. Chang, Prajnan Das, Y. Nancy You
Journal: Journal of Clinical Oncology (2023)

3618 Background: The rise in young-onset rectal cancer (YORC) calls for better understanding of the long-term impact of radiation therapy(RT) on gastrointestinal(GI) toxicity and pelvic organ function. We aimed to prospectively capture the longitudinal trajectories of patient-reported outcomes(PROs) in YORC patients who received RT vs. no RT and to identify factors associated with unfavorable PROs. Methods: We prospectively enrolled 120 YORC patients undergoing curative-intent treatment. The validated EORTC QLQ-CR29 was self-administered at time intervals grouped as: 0-11 months, 12-23 months, and 24+ months post-resection. Responses were stratified by receipt of neoadjuvant RT (yes vs. no). The longitudinal change in PROs was described by a linear mixed effects model. Multivariate linear regression was used to determine the impact of treatment factors on long-term PROs. Results: The median age at diagnosis was 44. The majority (N = 92, 77%) presented with cT3,4/N+ disease. Preoperative therapy included: no RT (N = 38, 32%; 8 [7%] who received chemotherapy alone, and 30 [25%] who received no neoadjuvant therapy), vs. RT (N = 82, 68%; where 59 [72%] also received concurrent capecitabine). More patients in the RT group had advanced T stage (3 or 4; 94% vs. 56%, P&lt; 0.001), distal tumor (median 7 vs. 12.5 cm from the anal verge, P&lt; 0.01), and underwent abdominal perineal resection (19 vs. 0%, P&lt; 0.001). After a median follow-up of 70 months, all were alive: 103 (86%) were disease-free, 9 (8%) had recurrence with successful salvage, and 8 (7%) had disease progression. In the RT group, sore skin improved at 12-23 and 24+ months (Estimate [ B]: -16.5, P= 0.03 and B: -14.4, P= 0.03), dyspareunia improved at 12-23 months ( B: -31.8, P&lt; 0.01), and blood/mucus in stool improved at 24+ months ( B: -8.01, P&lt; 0.01) vs. 0-11 months. At 24+ months, RT receipt was associated with worse stool frequency ( B: 26.4, P&lt; 0.01), urinary frequency ( B: 18.4, P= 0.04), and flatulence ( B: 23.0, P= 0.02). Conclusions: YORC often require multimodality therapy including RT. Sore skin, dyspareunia, and blood/mucus in stool improved, but flatulence and frequency can persist beyond 2 years post RT. Proactive counseling and supportive measures are needed to inform treatment choices and mitigate long-term impact. [Table: see text]
Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for human uterine sarcoma cells.
Authors: Mervat Mostafa Omran, Somayeh Vafaei, Ayman Al-Hendy, Qiwei Yang
Journal: Journal of Clinical Oncology (2023)

e17620 Background: Uterine sarcoma is strongly associated with poor prognosis, high rates of recurrence, and metastasis. However, the molecular mechanisms underlying the origin and development of uterine sarcoma and treatment options are limited. Enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDACs) play an important role in cancer progression. This study aimed to assess the effect of targeting both EZH2 and HDACs on the phenotype of uterine sarcoma (US) cells. Methods: Tazemetostat (EPZ-6438, E7438), a potent, and selective EZH2 inhibitor, was first approved by the US Food and Drug Administration (FDA) in 2020. Entinostat (MS-275, SNDX-275) is one of the strong inhibitors for HDAC1 and HDAC3, Vorinostat is used to treat cutaneous T-cell lymphoma, Tucidinostat (Chidamide, HBI-8000, CS-055) is a low nanomolar inhibitor of HDAC1, 2, 3, and 10. Uterine sarcoma cell line (MES-SA) was treated with different concentrations (1.56-200 mM) of Tazemetostat and/or Entinostat, Vorinostat, Tucidinostat (Chidamide). for 24, 48, 72 h, respectively. Further mechanistic confirmation was carried out on best combination in both 2D and 3D culturing using IHC and real time PCR. Results: Our data showed that Entinostat synergistically (with a combination index 0.539) augments the cytotoxic activity of Tazemetostat in both 2D and spheroids in vitro model systems. The IC50 values for Tazemetostat were significantly reduced to 4.5 mM after combination treatment with 6.25 mM Entinostat for 48 h. Entinostat enhanced the antiproliferative effect of Tazemetostat with a decrease in the expression of proliferative markers Ki67(P &lt; 0.0001) and PCNA (P &lt; 0.01). Furthermore, combination treatment significantly increased US cell apoptosis, concomitantly with increased both BAX and Caspase-3 levels and decreased Bcl-2 (P &lt; 0.0001) using 2D and spheroid in vitro model (P &lt; 0.001). The finding was confirmed by IHC analysis in the US cell-derived spheroids. Conclusions: Our studies demonstrate that Entinostat, in combination with Tazemetostat proves significantly superior to either single treatment. Dual targeting EZH2 and HDACs may provide a promising treatment option for this aggressive cancer disease.